The present invention is directed to a new process for the preparation of 1-substituted diaryl-4-amino-piperidinyl compounds. In further aspects, the present invention also relates to new intermediates used in said process.
WO 98/28270 discloses a group of compounds, and processes for their preparation, to which 1-substituted diaryl-4-amino-piperidinyl compounds belongs.
WO 99/33806 discloses 4[aryl(piperidin-4-yl)]aminobenzamide compounds and processes for their preparation. The core of the process disclosed in WO99/33806 consists of a reductive amination followed by a second step wherein the previously prepared N-aryl-piperidineamine is reacted with a bromo, iodo or trifluoromethanesulfonyloxy substituted benzamide in the presence of a palladium catalyst a phosphine ligand and a base to give said (N-aryl, N-piperidin-4-yl)aminobenzamide.
The first reaction step (reductive amination) is performed using an appropriate solvent/reducing agent combination such as 1,2-chloroethane or acetonitrile/NaBH(OAc)3+acid catalyst; methanol/NaBH3CN+acid catalyst; titanium isopropoxide/NaBH3CN; methanol, ethanol or isopropanol/NaBH4; alcoholic solvent/H2+noble metal catalyst or 1,2-dichloroethane or acetonitrile/NaBH(OAc)3+acid catalyst. The product of the first step is thereafter isolated and purified before the second step is performed. The second step is thereafter performed in a different solvent.
Thomas et al. in J. Med. Chem. discloses 4-[aryl(piperidin-4-yl)]aminobenzamide of similar structure as WO 99/33806. The compounds are prepared by a reductive amination step followed by a nucleophilic aromatic substitution step.
The process of the present invention provides 1-substituted diaryl-4-amino-piperidinyl compounds in an improved and simplified manufacturing process that, e.g. uses only commercially available starting materials and reagents, has less reaction and purification steps, gives easier purification of the final and intermediate compounds, uses only one solvent system throughout the whole process.
Thus, the object of the present invention is to provide a novel process suitable for use in large-scale synthesis. A further object of the present invention is to provide a process containing as few reaction steps as possible.
The present invention provides a new process for preparation of 1-substituted diaryl-4-amino piperidinyl compounds, hereinafter referred to as compounds of the invention. The compounds of the invention are useful in therapy, and in particular for the treatment of pain.
The process for preparing of 1-substituted diaryl-amino-piperidinyl compounds is schematically shown in Scheme 1 below. 
wherein
R1 and R2 are independently selected from the group consisting of hydrogen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyl, C1-C6 acyloxy, cyano, amino, nitro, C1-C6 acylamino, C1-C6 alkylamino, (C1-C6 alkyl)2amino, C1-C6 alkylthio, C1-C6 alkylsulfonyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, COxe2x80x94NR8R9 and C1-C6 alkoxycarbonyl;
R3, R4, R5 and R6 are independently selected from hydrogen and C1-C6 alkyl;
R7 is selected from the group consisting of imidazolyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl and phenyl, all optionally and independently mono-, di-, or tri-substituted with a Rxe2x80x2 group;
R8 and R9 are independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, phenyl, benzyl, all optionally and independently mono-, di-, or tri-substituted with a Rxe2x80x3 group;
Arxe2x80x94 is phenyl, 1-naphthyl or 2-naphthyl, each optionally substituted with 0 to 3 R2 groups;
Rxe2x80x2 is independently selected from the group consisting of hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyl, C1-C6 acyloxy, cyano, amino, nitro, C1-C6 acylamino, C1-C6 alkylamino, (C1-C6 alkyl)2amino, C1-C6 alkylthio, C1-C6 alkylsulfonyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy;
Rxe2x80x3 is independently selected from the group consisting of hydroxy, halogen, C1-C6 alkyl C1-C6 alkoxy, cyano, amino, nitro, C1-C6 alkylthio, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy; and
n is 1, 2, 3, 4, 5, or 6.
A preferred embodiment of the present invention is the process according to Scheme 1, wherein
R1 and R2 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, halogen, cyano, amino, COxe2x80x94NR8R9 and C1-C6 alkoxycarbonyl;
R3, R4, R5 and R6 are independently selected from hydrogen and C1-C4 alkyl;
R7 is selected from the group consisting of imidazolyl, thienyl, furanyl, pyridinyl, and phenyl;
R8 and R9 are independently selected from hydrogen, C1-C6 alkyl, phenyl or benzyl; and
n is an integer from 1 to 6.
A more preferred embodiment of the present invention is the process according to Scheme 1, wherein
R1 and R2 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, halogen, cyano, amino, COxe2x80x94NR8R and C1-C6 alkoxycarbonyl;
R3, R4, R5 and R6 are hydrogen;
R7 is selected from the group consisting of imidazolyl, furanyl, pyridinyl, and phenyl;
R8 and R9 are independently selected from hydrogen, ethyl and isopropyl, and
n is 1.
An even more preferred embodiment of the present invention is the process according to Scheme 1, wherein
R1 and R2 are independently selected from hydrogen, hydroxy, halogen, cyano, amino, COxe2x80x94NR8R9 and C1-C6 alkoxycarbonyl;
R3, R4, R5 and R6 are hydrogen;
R7 is selected from the group consisting of imidazolyl, furanyl, pyridinyl, and phenyl;
R8 and R9 are independently selected from hydrogen, ethyl and isopropyl, and
n is 1.
Most preferred embodiment of the present invention is the process according to Scheme 1, wherein
R1 and R2 are independently selected from hydrogen, halogen, cyano COxe2x80x94NR8R9 and C1-C6 alkoxycarbonyl;
R3, R4, R5 and R6 are hydrogen;
R7 is selected from the group consisting of imidazolyl, pyridinyl, and furanyl;
R8 and R9 are independently selected from hydrogen, ethyl and isopropyl; and
n is 1.
Thus the process of the present invention can be described as comprising a one-pot double arylation step. It will be apparent for the skilled person that an optional deprotection step might have to be introduced after the one-pot double arylation step, due to interference/reactivity of the substituents. Reference is made to xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd edition, T. W. Greene and P. G. M. Wutz, Wiley-Interscience (1991). Example of a substituent that might need to be protected is hydroxy. A hydroxy substituent preferably protected as its methyl ether. Such methyl ether would then have to be cleaved after the one-pot double arylation step. This could for example be done by treating the product of the one-pot double arylation step with BBr3 under standard conditions, such as 2-5 molar equivalents of BBr3 in dichloromethane at xe2x88x9278xc2x0 C.
The One-Pot Double Arylation Step
A one-pot double arylation step is a reaction that is performed in one pot but consists of two separate and distinct reaction steps (arylation couplings) that are performed consecutively without the need for any purification of intermediate compounds, work-up procedure, or change of solvent. The two reagents are added separately and the addition of the reagents is so timed as to allow the first reaction step to be completed before the next reagent is added to start the second reaction step.
The one-pot double arylation step of the present invention is performed by reacting 4-amino-piperidine of Formula II 
wherein R3 to R7, n, and Rxe2x80x2 are as described above in Scheme 1, with a first bromo compound of Formula III, 
wherein R1, R8, R9, and Rxe2x80x3 are as decribed above in Scheme 1, in the presence of a strong base, a palladium catalyst and a phosphine ligand. Upon completion of the first arylation step, a second bromo compound of Formula I 
wherein R1, R8, R9, Rxe2x80x3 and Ar are as decribed above in Scheme 1, and a strong base are added, without any isolation or purification of the reaction product of the first reaction step, to give the final product of Formula I in high yield. 
wherein R1 to R9, Ar, Rxe2x80x2, Rxe2x80x3 and n are as described above in Scheme 1. The final product might optionally have to been taken through a deprotection step.
Each reaction step of the one-pot double arylation in preferably done in an inert non-polar solvent system, such as toluene, at elevated temperature, such as around 80xc2x0 C. or reflux, and for a few hours.
Palladium catalysts to be used in process of the present invention is chosen from a group consisting of PdCl2, Pd(OAc)2, Pd(Ph3P)4(O) and tris(dibenzylideneacetone)-dipalladium(O), of which the last is preferred.
Phosphine ligands to be used in process of the present invention is chosen from a group of tri(o-tolyl phosphine), xantphos, 2-(di-t-butylphosphino)biphenyl and racemic BINAP, of which the latter is preferred.
Examples of strong bases that can be used in the process of the present invention comprise, but is not limited to, sodium tert. butoxide, cesium carbonate and sodium methoxide, of which sodium tert. butoxide is preferred.
The one-pot double arylation of the present invention is thus done without any isolation or purification of intermediate compounds. The one-pot double arylation of the present invention is further done in one solvent system for both arylation steps to Possible as well as preferred amounts and reaction conditions in the one-pot double arylation step are the following.
The molar equivalents relative to 4-aminopiperidine compound are for,
It is also recommended to have the molar ratio between palladium catalyst and phosphine reagent as close to 1 as practically possible and the molar ratio between 2nd bromo compound and the second addition of base as close to 1 as practically possible.
The Deprotection Step
The optional deprotection can be accomplished by any known standard method to remove protecting groups that do not degrade the other parts of the molecule of the present invention. Reference is made to xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd edition, T. W. Greene and P. G. M. Wutz, Wiley-Interscience (1991).
The final product prepared according to the process of the present invention may thereafter be taken through further standard additional purification steps and/or converted into a suitable pharmaceutically acceptable salt.
It has also surprisingly been found that the two separate and distinct reaction steps (arylation couplings) can be performed in any order. This means that the process of the present invention can also be performed as is shown below in Scheme 2. 
Intermediates
Another object of the present invention is to provide new intermediates that can be used in the preparation of compound of formula I.
Accordingly, a further aspect of the present invention is intermediate compound of Formula V and VI shown below, 
wherein R1 to R9, Ar, Rxe2x80x2, Rxe2x80x3 and n are as described in all the embodiments above.
The compounds prepared by the present invention can thereafter be converted into a pharmaceutically acceptable salt thereof, or optionally one of the substituents R or R can be converted into another functional group as described in Larock, Richard; Brown H. C.; Comprehensive Organic Transformations: A Guide to Functional Group Preparations, New York: VCH (1989), ISBN #-0471187186.
In one embodiment of the present invention R1 is C1-C6 alkoxycarbonyl, e.g. tert. butyl ester, and R2 to R9, Ar, Rxe2x80x2, Rxe2x80x3 and n are as described in all the embodiments above. The R1C1-C6 alkoxycarbonyl group is eventually converted into a carboxamido group, e.g.
N,N-diethylcarboxamido, using standard procedure, e.g. by treating the ester with the corresponding amine in a suitable solvent.
In a preferred embodiment of the present invention R is N,N-diethylcarboxamido or N,N-diisopropylcarboxamido.
In a preferred embodiment of the present invention R2 is independently selected from hydroxy, carboxamido, and halogen.
In a preferred embodiment of the present invention R3, R4, R5, and R6 are all hydrogen.
In a preferred embodiment of the present invention n is 1 and R7 is a imidazolyl, furanyl, pyridinyl, or phenyl group.